Type 2 diabetes is characterized by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with microvascular, macrovascular, and neuropathic complications. Thus, the regulation of blood glucose is the major target for the management of type 2 diabetes, which can prevent the development of complications and improve the quality of life.
In type 2 diabetes, hyperglycemia results from metabolic abnormalities including insulin resistance, defects in glucose-stimulated insulin secretion, and excessive hepatic glucose output (1). In most genetically predisposed individuals, there is a slow progression from a normal state to insulin resistance, hyperinsulinemia, glucose desensitization, defects in insulin secretion, impaired glucose tolerance, and then to hyperglycemia (2).
Impaired glucose transport is one of the major factors contributing to insulin resistance in type 2 diabetic patients (3). The ability of insulin to mediate tissue glucose uptake is a critical step in maintaining glucose homeostasis and in clearing the post-prandial glucose load (4,5). Glucose transport is mediated by specific carriers called glucose transporters (GLUTs), and insulin-stimulated glucose transport is mediated largely by GLUT4 (6). Binding of insulin to its receptor activates the receptor's tyrosine kinase activity, which phosphorylates a number of downstream substrates such as insulin receptor substrate-1 (IRS-1) and IRS-2. Phosphorylated IRS-1 and -2 bind to a variety of other substrates and trigger insulin action, such as glucose uptake (7,8).
Herbal plants have been used for medicinal purposes for centuries. For example, Cinnamon, widely consumed as a beverage in Asian countries, is known to have a glucose lowering effect (9,10) and prevent type 2 diabetes (11). And it was shown that the basal and insulin-stimulated glucose uptake of rat adipocytes was increased by green tea (12).
Pharmacological agents that enhance glucose transport are useful for lowering blood glucose levels in type 2 diabetic patients. In the present invention, the present inventors synthesized small molecules based on the anti-diabetic components of cinnamon and screened them for glucose transport activity. One of these, an ester derivative of 3,4-dihydroxyhydrocinnamic acid, designated DHH105, most significantly increased glucose transport. And the present inventors found out that the compound is very useful as an anti-diabetic agent, since the compound has blood glucose lowering effects in vivo as a result of enhancing insulin signaling and subsequent glucose transport.